Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy

Pathogenic homozygous variations in ACTL6B cause DECAM syndrome: Developmental delay, Epileptic encephalopathy, Cerebral Atrophy, and abnormal Myelination

“…Previous reports have suggested that microcephaly with or without minimally simplified gyral pattern are part of the phenotypic spectrum of ACTL6B ‐related phenotype (Fichera et al, ; Maddirevula et al, ). In contrast to these findings, no evidence neither for simplified gyral pattern nor microcephaly was detected in the present study.…”

“…Most recently, Fichera et al () reported c.820C > T and c.1045G > A variants in two unrelated, nonconsanguineous families having affected children (III:3 and III:4 from Family A and II:5 from Family B) with developmental and epileptic encephalopathy phenotype.…”

“…In contrast to these findings, no evidence neither for simplified gyral pattern nor microcephaly was detected in the present study. More recently, white matter abnormalities on MRI have been described variably as widespread hypomyelination or delayed myelination (Fichera et al, ). All cases have varying degrees of cerebral white matter atrophy and volume loss in frontotemporal region, and two cases have cerebellar vermis atrophy.…”

Scientific evaluation of negative exome sequencing followed by systematic scoring of candidate genes to decipher the genetics of neurodevelopmental disorders

“…To demonstrate the utility of this score, we list below the candidates with CaSc ≥ 9 (top 15%); TANC2, GLS, ASIC1A, KMT2E, ACTL6B, GRIN3B, SPEN, DNAH14, CUX1, PUM1, UNC13A, RASGRP1, GRIA4, SLC32A1, PUM2, TOB1, MAPK8IP3, NPTX1, ETV5, CACNB4, WDFY3 (for a detailed list of all candidates, see Table S2). Fourteen of these were published or funneled into subsequent validation studies 21–29 ( TANC2, KMT2E , and WDFY3 are under review, but still unpublished data). Of the 158 candidate variants, most were de novo (n=74, 47%, of these 71 are autosomal, 3 are X linked), followed by autosomal recessive (n=68, 43%, of these 41 are compound heterozygous, and 27 are homozygous, mostly (n=22) observed in consanguineous families), and inherited variants (n=15, 9%, are X linked and one is an autosomal, paternally inherited heterozygous variant) (Figure 2 and Tables S1 and S2).…”

“…Considering all 23 candidate variants (in 21 genes) with scores of 9.0 or more (equivalent to top 15%) revealed that at least 14 of them (TANC2, GLS, KMT2E, ACTL6B, GRIN3B, SPEN, CUX1, PUM1, UNC13A, GRIA4, SLC32A1, PUM2, MAPK8IP3, WDFY3) are already published or funneled into projects with several other patients and often with functional analyses 21–29 (as of 15 th of February 2019, see also Figure 3) ( TANC2, KMT2E , and WDFY3 are under review, but still unpublished data). For the remaining seven genes ASIC1, DNAH14, RASGRP1, TOB1, NPTX1, ETV5 , and CACNB4 there is partly good supporting evidence in the literature or via GeneMatcher 30 , but further analyses are necessary.…”